It is considered that the progressive and delayed death of nerve cells, observed in cerebral injury and cerebrovascular disease such as intracerebral hemorrhage, transient cerebral ischemia, and cerebral infarction, is mainly caused by the increase of the intracellular Ca2+ concentration, the various factors of which are related to signal transduction to cause, for example, the abnormal activation of receptors by over releasing glutamate which is internal excitability, the activation of ion channels, and the induction of reactive oxygen species/free radicals. [F. B. Meyer, Brain Res. Rev., 14, 227 (1989); E. Boddeke et al., Trends Pharmacol. Sci., 10, 397 (1989); J. M. McCall et al., Ann. Rep. Med. Chem., 27, 31 (1992)].
From these points of view, antagonists for glutamate receptors, calcium channel blockers antioxidants and so on have been applied for medicaments of preventing or suppressing the neurodegeneration. However, these clinically used medicaments suppress only a few pathways relating to the increase of the cellular Ca2+ concentration, and therefore are not yet sufficient enough for preventing or suppressing the neurodegeneration.
On the contrary, the internal production of CalbindinD-28k is induced by activation of receptors for many physiologically active substance's such as FGF, LT-3, NT-4/5, BDNF, IGF-I/II, PDGF, estrogen and so on, and as well as by activation of FGF receptor, which is one of nerve growth factor receptors [C. V.-Abejon et el., Neuron, 15, 105 (1995); A. Silva et al., Brain Res. Bull., 1, 35 (2000)]. And CalbindinD-28k, one of Ca2+-binding proteins and mainly distributed in vulnerable site against ischemic disorders in the central nervous system, which is known to show buffer action against the increase of intracellular Ca2+ concentration. [A. M. Lacopino et al., Neurodegeneration, 3, 1 (1994); M. P. Mattson et al., Neuron, 6, 41 (1991)]
Accordingly, it is expected to achieve sufficient neuroprotective effects against the increase of intracellular Ca2+ concentration caused by any kinds of pathways if CalbindinD-28k, one of the Ca 2+-binding proteins per se, can be supplied in a cell. Namely, it is expected that medicaments containing CalbindinD-28k would be extremely effective therapeutic and improving agents against cerebral functional and due to various ischemic disorders such as cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis. It is also expected to be effective against cerebral dysfunction due to cerebral ischemic disorders due to sequelae of senile dementia, cerebral injury and surgical operation, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and so on.
However, it is very difficult and therefore it is not likely to administer the CalbindinD-28k protein directly into the desirable site in the central nervous system of a body in view of the limitations existing in the pharmacological and pharmaceutical methodology because CalbindinD-28k itself is an unstable macro molecular weight protein having 28 Kd (Kilo Dalton) of molecular weight.
On the other hand, the lower molecular weight compounds capable of inducing the production of CalbindinD-28k protein can be easily prepared into the various kinds of pharmaceutical compositions by the conventional technique. Therefore, these lower molecular weight compounds would induce the production of the neuroprotective CalbindinD-28k protein once easily administered into a body, showing the buffering action against the increase of the intracellular Ca2+ concentration. That is, these lower molecular weight compounds can be effective pharmaceutical compounds for improving and treating cerebral functional and organic disorders.
Under these circumstances, one objective of the present invention is to select and to provide the lower molecular-weight neuroprotective compounds capable of inducing the production of CalbindinD-28k, one kind of Ca2+-binding proteins, via phosphorylation of receptors of various physiologically active substances, as well as to provide the pharmaceutical compositions of low toxicity in suitable preparations such as intravenous injectable solution.
The other objective of the present invention is to provide the therapeutic and improving agents for cerebral functional disorders due to various ischemic disorders such as cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis, as well as cerebral organic disorders such as sequelae of senile dementia, cerebral injury. or surgical operation, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.